Abstract: The vast majority of cancer deaths result from the metastatic spread of cancer cells to distal organs. Systemic chemotherapy can prevent metastasis in some patients by killing microscopic tumor cells throughout the body. Chemotherapy can also dramatically reduce the size of metastases in some advanced stage patients. Interestingly, these standard chemotherapeutic regimens are administered to hundreds of thousands of patients without prior knowledge of the sensitivity of individual patients. cancer cells to such treatments. If we could identify the chemotherapeutic responsive and resistant subsets of patients at diagnosis, innumerable patients would be spared from the risks, side effects, and expense of ineffective chemotherapy and instead offered alternative and experimental therapies in the upfront setting. Furthermore, the identification of such biomarkers could provide mechanistic insights into the molecular underpinnings of chemotherapeutic resistance. Working in breast cancer, we recently discovered a set of human microRNAs that strongly suppress metastasis in a robust mouse model of breast cancer. These microRNAs act as biomarkers since their expression levels in primary tumors predict future metastatic relapse, thus guiding clinical decision-making. Colorectal cancer is a highly prevalent and aggressive disease entity with significantly fewer treatment options than breast cancer. We propose to apply a conceptually and technically innovative, systematic, and multi-disciplinary approach to discover .chemotherapeutic-response predictive microRNAs. through an experimental approach that integrates molecular, in vitro, in vivo, and human clinical insights. We will validate the power of these microRNA biomarkers through prospective in vivo human studies. If successful, we envision this powerful approach applied to other common cancers. The identification of such microRNAs will not only be of tremendous clinical value now, it will also lay the foundation for future mechanistic and synthetic efforts aimed at generation of novel microRNA-based therapeutic agents for the prevention and treatment of cancer metastasis. Public Health Relevance: Colorectal cancer is a highly prevalent and aggressive disease entity. Despite surgical resection of primary tumors, tens of thousands of patients will develop metastatic spread of their cancers to organs such as the liver or lung and will consequently die of their disease. Through a multi-disciplinary, collaborative, and highly innovative approach that integrates molecular, in vitro, in vivo, and human clinical analyses, we propose to discover specific microRNA biomarkers that will empower clinicians to identify patients whose tumors will display resistance to standard chemotherapy for colorectal cancer. The identification of such biomarkers will save thousands of patients annually from ineffective treatment and make them eligible for alternative and experimental therapies. The identification of such miRNA biomarkers will not only be of tremendous clinical diagnostic value now, but will lay the foundation for future efforts aimed at generating novel microRNA-based therapeutic agents for the prevention and treatment of colorectal cancer metastasis.